Department of Allergy and Immunology. Drug allergy. Dean Tey Paediatric Allergist & Immunologist FRACP LECTURE 2014

Transcription

1 Drug allergy Dean Tey Paediatric Allergist & Immunologist FRACP LECTURE 2014

2 Outline 1. Background 2. SCAR 3. Mechanism of action 4. Assessment on history 5. Investigations 6. Drug desensitisation 7. Specific drugs

3 Outline 1. Background 2. SCAR 3. Mechanism of action 4. Assessment on history 5. Investigations 6. Drug desensitisation 7. Specific drugs

4 Adverse drug reactions WHO 1966 definition 1 An adverse drug reaction is any noxious, unintended, undesired effect of a drug Occurring at doses used in humans for prevention, diagnosis or treatment Hospitalised patients 15.1% of patients Nearly half being serious in nature 1 Fatal ADRs in 0.32% Outpatients 17-25% of patients More than half being serious in nature 2,3 1. World Health Organization. International drug monitoring: the role of the hospital. Geneva: The Organization; Lazarou et al. JAMA 1998;279: Gandhi et al. J Gen Intern Med 2000;15:149-54; 4. Gandhi et al. N Engl J Med 2003;348:

5 Epidemiology IgE mediated drug allergy Penicillin allergy Self-reported versus post-assessment Rate of self-reported penicillin allergy is 10% 1 Following evaluation > 90% are able to tolerate drug 2,3 Why bother? More likely to be treated with expensive, broad-spectrum antibiotics 4 This can lead to development and spread of multi-drug resistant bacteria 1. Solensky, R. (2003). Clinical Reviews in Allergy & Immunology 24(3): Sogn, D. D., R. Evans, 3rd, et al. (1992). Archives of Internal Medicine 152(5): Gadde, J., M. Spence, et al. (1993). JAMA 270(20): Solensky, R., H. S. Earl, et al. (2000). Annals of Allergy, Asthma, & Immunology 84(3):

6 Liew WK, Williamson E and Tang MLK. Anaphylaxis fatalities and admissions in Australia. J Allergy Clin Immunol 2009;123: National database analysis of anaphylaxis deaths and hospital admissions in Australia over 8 years ( ) 2. Peak age-specific hospital admissions rates were for the year age group

7 Liew WK, Williamson E and Tang MLK. Anaphylaxis fatalities and admissions in Australia. J Allergy Clin Immunol 2009;123: Most deaths (73%) occurred in adults > 55 yo; all penicillin-induced deaths occurred between persons years of age 2. Significant co-morbidities included : a) ischaemic heart disease or dysarrhythmias (n = 21), b) obstructive airway disease (n = 11), c) mastocytosis (n = 1) and d) hypogammaglobulinemia (n = 1)

8 Liew WK, Williamson E and Tang MLK. Anaphylaxis fatalities and admissions in Australia. J Allergy Clin Immunol 2009;123: Food-induced anaphylaxis admissions Estimated multiplicative rate increase of 1.12 per year (P < ) Drug-induced anaphylaxis admissions 1. Estimated multiplicative rate increase of 1.06 per year (P < ) 2. Equivalent to an increase of 150%

9 Liew WK, Williamson E and Tang MLK. Anaphylaxis fatalities and admissions in Australia. J Allergy Clin Immunol 2009;123: Food-induced anaphylaxis fatalities No increase Drug-induced anaphylaxis fatalities Increased by 300%

10 Outline 1. Background 2. SCAR 3. Mechanism of action 4. Assessment on history 5. Investigations 6. Drug desensitisation 7. Specific drugs

11 Adverse drug reactions Types of adverse drug reactions Rawlins et al. Mechanisms of adverse drug reactions. In: Davies DM, editor. Textbook of adverse drug reactions. New York: Oxford University Press; P

12 Torres MJ and Blanca M. Med Clin N Am 94 (2010)

13 Pichler WJ. Immune mechanism of drug hypersensitivity. Immunol Allergy Clin N Am 24 (2004)

14 SCARs Severe cutaneous adverse reactions Comprises of: 1. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 2. Acute generalised exanthematous pustulosis (AGEP) 3. Hypersensitivity syndrome (HSS) Drug reaction with eosinophilia and systemic symptoms (DRESS) Drug-induced hypersensitivity syndrome (DiHS) Mockenhaupt M. Epidemiology and causes of severe cutaneous adverse reactions to drugs. In Pichler WJ, editor. Drug hypersensitivity. Basel, Karger, 2007, pp

15 SCARs Severe cutaneous adverse reactions Comprises of: 1. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 2. Acute generalised exanthematous pustulosis (AGEP) 3. Hypersensitivity syndrome (HSS) Drug reaction with eosinophilia and systemic symptoms (DRESS) Drug-induced hypersensitivity syndrome (DiHS) Mockenhaupt M. Epidemiology and causes of severe cutaneous adverse reactions to drugs. In Pichler WJ, editor. Drug hypersensitivity. Basel, Karger, 2007, pp

16 SJS Time course Prodromal illness of fever, sore throat and conjunctivitis for 1-3 days. Mucosal lesions appear, followed by cutaneous lesions. Cutaneous lesions AKA Erythema multiforme (target lesions) Begin as erythematous macules with dusky centres Flacid blisters then appear as the necrotic epidermis detaches from the dermis 1. Chia et al. Curr Opin Allergy Clin Immunology 2007;7: Bircher et al. Toxicol 2005;209:

17 SJS Prominent mucosal lesions Conjunctiva Oral mucosa Genital mucosa Trachea, bronchi Gastrointestinal tract Systemic features High fevers Lymphadenopathy Arthralgia Arthritis 1. Chia et al. Curr Opin Allergy Clin Immunology 2007;7: Bircher et al. Toxicol 2005;209:

18 1. Bircher et al. Toxicol 2005;209:

19 Spectrum of SJS and TEN SJS < 10% of BSA SJS/TEN 10-30% of BSA TEN > 30% of BSA 10% 30% 50% MORTALITY 1. Mockenhaupt M. Epidemiology and causes of severe cutaneous adverse reactions to drugs. In Pichler WJ, editor. Drug hypersensitivity. Basel, Karger, 2007, pp Mockenhaupt et al. Allergy Clin Immunol Int 2002; 14:

20 SJS and TEN Culprit high-risk drugs 1. Anti-infective sulphonamides: cotrimoxazole, sulfasalazine, sulfadiazine, sulfadioxine, sulfafurazole 2. Allopurinol 3. Antiepileptics: carbamazepine, lamotrigine, phenytoin, phenobarbital 4. Oxicam-NSAIDs: meloxicam, piroxicam, tenoxicam 5. Nevirapine Not associated 1. Beta-blockers 2. ACE inhibitors 3. Calcium channel blockers 4. Sulphonamide-relate diuretics 5. Sulfonylurea antidiabetics 6. Insulin 7. Propionic acid NSAIDs Mockenhaupt, M., C. Viboud, et al. (2008). "Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study." Journal of Investigative Dermatology 128(1):

21 SCARs Severe cutaneous adverse reactions Comprises of: 1. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 2. Acute generalised exanthematous pustulosis (AGEP) 3. Hypersensitivity syndrome (HSS) Drug reaction with eosinophilia and systemic symptoms (DRESS) Drug-induced hypersensitivity syndrome (DiHS) Mockenhaupt M. Epidemiology and causes of severe cutaneous adverse reactions to drugs. In Pichler WJ, editor. Drug hypersensitivity. Basel, Karger, 2007, pp

22 Acute generalised exanthematous pustulosis (AGEP) Also known as Toxic pustuloderma Pustular drug rash Pustular psoriasiform eruption with leukocytosis Characterised by Acute appearance of dozens of pustules, on the background of oedematous erythema Pustules are sterile, nonfollicular, pinhead-sized Mockenhaupt M. Epidemiology and causes of severe cutaneous adverse reactions to drugs. In Pichler WJ, editor. Drug hypersensitivity. Basel, Karger, 2007, pp

23 Mockenhaupt M. Epidemiology and causes of severe cutaneous adverse reactions to drugs. In Pichler WJ, editor. Drug hypersensitivity. Basel, Karger, 2007, pp Acute generalised exanthematous pustulosis (AGEP) Clinical features (cont) Accentuated in main folds Facial oedema Rarely mucous membrane involvement Systemic symptoms e.g. fever, leucocytosis

24 Acute generalised exanthematous pustulosis (AGEP) Typical time course Skin symptoms arise rapidly (hours) Resolve quickly (within days) without treatment Time of onset Antibiotics: 1 day All other associated drugs: 11 days 1. Mockenhaupt M. Epidemiology and causes of severe cutaneous adverse reactions to drugs. In Pichler WJ, editor. Drug hypersensitivity. Basel, Karger, 2007, pp Sidoroff et al. J Invest Dermatol 2003; 12: 121

25 Acute generalised exanthematous pustulosis (AGEP) Aetiology Antimicrobials: pristinamycin, aminopenicillins, quinolones, sulphonamides, terbinafine Hyrdroxychloroquine Diltiazem Complications Rare Usually in elderly or patients with poor medical health Amongst 97 patients with validated cases of AGEP, death rate was 4% 1. Mockenhaupt M. Epidemiology and causes of severe cutaneous adverse reactions to drugs. In Pichler WJ, editor. Drug hypersensitivity. Basel, Karger, 2007, pp Sidoroff et al. J Invest Dermatol 2003; 12: 121

26 SCARs Severe cutaneous adverse reactions Comprises of: 1. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 2. Acute generalised exanthematous pustulosis (AGEP) 3. Hypersensitivity syndrome (HSS) Drug reaction with eosinophilia and systemic symptoms (DRESS) Drug-induced hypersensitivity syndrome (DiHS) Mockenhaupt M. Epidemiology and causes of severe cutaneous adverse reactions to drugs. In Pichler WJ, editor. Drug hypersensitivity. Basel, Karger, 2007, pp

27 Hypersensitivity syndrome (HSS) Traditionally used to summarise numerous severe drug reactions 1,2 More recently, 2 other denominations were created 3,4 Drug rash with eosinophillia and systemic symptoms (DRESS) Drug induced Hypersensitivity Syndrome (DiHS) 1. Shear and Spielberg 1988; 2. Peyriere, Dereure et al. 2006; 3. Bocquet, Bagot et al. 1996; 4. Seishima, Yamanaka et al. 2006

28 HSS/DRESS/DiHS Clinical features Diagnosis of exclusion Variable presentation High fever is usually first noted Then widespread skin rash: erythematous, papular and pustular Also Multi-organ involvement Eosinophilia

29 HSS/DRESS/DiHS Timing Onset usually later: 2-8 weeks after therapy started Duration usually longer This makes recognition of drug as a cause difficult Culprit drugs Aromatic anticonvulsants: carbamazepine, phenytoin, phenobarbitone Others: minocycline, allopurinol, thalidomide, sulfonamides, antiretrovirals 1. Kardaun, Sidoroff et al British Journal of Dermatology 156(3): Shear and Spielberg 1988; Journal of Clinical Investigation 82(6): Bocquet, Bagot et al. 1996; Seminars in Cutaneous Medicine & Surgery 15(4): Khan et al. 2010; Journal of Allergy and Clinical Immunology 125:S

30 SCARs Severe cutaneous adverse reactions Take home points Important to recognise these conditions Although rare, high morbidity and mortality Presents as a contraindication to skin testing and drug provocation testing

31 Pharmaco-genetics 1. Phillips et al. Drug hypersensitivity: Pharmacogenetics and clinical syndromes. JACI 2011; 127:S60-S66.

32 Outline 1. Background 2. SCAR 3. Mechanism of action 4. Assessment on history 5. Investigations 6. Drug desensitisation 7. Specific drugs

33 Pathogenesis Low molecular weight drugs High molecular weight drugs Metabolised or bioactivated Spontaneously degrade e.g. penicillin Drug reaction via: 1. Binding to nucleic acids produce altered gene product 2. Binding to macromolecules cause direct cellular damage 3. Binding covalently to larger macromolecules form immunogenic complex and induce immune response (haptenization) 1. Park, B. K., J. W. Coleman, et al. (1987). "Drug disposition and drug hypersensitivity." Biochemical Pharmacology 36(5): Solensky, R. (2006). "Drug hypersensitivity." Medical Clinics of North America 90(1):

34 Outline 1. Background 2. SCAR 3. Mechanism of action 4. Assessment on history 5. Investigations 6. Drug desensitisation 7. Specific drugs

35 History What was the name of the medication? Penicillin vs amoxycillin vs augmentin Underlying illness E.g. Cellulitis versus viral upper respiratory tract infection Time course and duration of symptoms Rash appearance Mucous membrane involvement? Urticarial vs bullous vs exfoliative vs morbiliform? Systemic involvement Gastrointestinal, respiratory, arthropathy, fever 1. Solensky, R. (2006). "Drug hypersensitivity." Medical Clinics of North America 90(1): Khan et al. (2010). Drug allergy. Journal of Allergy and Clinical Immunology 125:S

36 History Concurrent medications prescribed? E.g. Narcotics, NSAIDs Previous course of same/similar medication? May suggest past sensitisation Previous episodes of similar symptoms in the absence of drug treatment? Suggestive of idiopathic urticaria 1. Solensky, R. (2006). "Drug hypersensitivity." Medical Clinics of North America 90(1): Khan et al. (2010). Drug allergy. Journal of Allergy and Clinical Immunology 125:S

37 Outline 1. Background 2. SCAR 3. Mechanism of action 4. Assessment on history 5. Investigations 6. Drug desensitisation 7. Specific drugs

38 Investigations Commonly performed 1. Skin prick test 2. Intradermal test 3. Drug provocation test (challenge) Less commonly used 1. Serum sige 2. Basophil activation assay 3. Patch testing

39 Investigations (less used) 1. Serum sige Detects antigen-specific IgE antibodies in subject s serum Most are not adequately validated Unclear specificity and sensitivity Difficult to bind drug allergens to solid-phase matrices Khan DA and Solensky R. Drug allergy. Journal of Allergy and Clinical Immunology 2010;125:s

40 Investigations (less used) 2. Basophil activation test Uses flow cytometry to quantify the expression of activation markers (CD63 or CD203C) on basophils after stimulation with an allergen 1 Currently there is only limited data using this method to evaluate patients with possible drug allergies 1 Diagnostic sensitivity and specificity is poor when directly compared to skin testing 2 1. Khan DA and Solensky R. Drug allergy. JACI 2010;125:s Hamilton RG and Adkinson NF Jr. In vitro assays for the diagnosis of IgE-mediated disorders. JACI 2004;114:

41 Investigations (less used) 3. Drug patch testing 1,2 Patches placed on the upper back Read at 20 minutes, with delayed readings at 48 hours, 96 hours and (if negative) 7 days. Might be useful for presumed non-ige delayed cutaneous drug reactions e.g. maculopapular exanthems, AGEP, fixed drug eruptions Not helpful for SJS or urticarial reactions 1. Khan DA and Solensky R. Drug allergy. JACI 2010;125:s Barbaud A. Drug patch testing in systemic cutaneous drug allergy. Toxicology 2005;209:

42 Investigations (common) Skin prick test Intradermal skin test Drug challenge

43 Intradermal skin testing A tuberculin, 0.5 ml insulin syringe or 1mL syringe with a 25- to 27-gauge needle is used ml of allergen is injected into the dermis, producing a 2- to 3-mmdiameter bleb Test is performed over the volar aspect of the forearm 1. Hamilton RG and Adkinson NF Jr. In vitro assays for the diagnosis of IgEmediated disorders. JACI 2004;114: Figure: Kranke B and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:

44 Intradermal skin testing Scoring method European Network for Drug Allergy (ENDA) position paper in Read at minutes after performance of test Positive if wheal increased by > 3 mm with an associated flare, when compared to initial wheal Alternate scoring system Positive intradermal test when any wheal diameter is > 5 mm This method has been used in a number of European studies 2,3,4,5 1. Torres et al. Diagnosis of immediate allergic reactions to beta-lactam antibiotics. Allergy 2003; 58: Blanca-Lopez et al. Allergy 2009: 64: ; 2. Romano et al. Allergy 2007: 62: 53-58; 3. Romano et al. Ann Intern Med 2004; 141: 16-22; 4. Mendelson et al. JACI 1984; 73:

45 Intradermal skin testing University Hospital of Montpellier, France 8.8% (13/998) of patients developed systemic reactions to skin tests performed for beta-lactams between Co Minh et al. JACI 2006; 117:

46 Drug challenge Gold standard for determining if a patient is tolerant or allergic to a particular drug Patient is admitted to hospital for 4 hours Graded doses of the index drug is administered, starting typically at 1/100 th of the final treatment dose Patient then completes the medication course at home Contraindications: SJS, TEN, DRESS Khan DA and Solensky R. Drug allergy. JACI 2010;125:s

47 Outline 1. Background 2. SCAR 3. Mechanism of action 4. Assessment on history 5. Investigations 6. Drug desensitisation 7. Specific drugs

48 Drug desensitisation New term is drug tolerance induction, as procedure is used for both IgE and non-ige mediated drug allergies Indicated where there is an absolute need for a particular drug and no suitable alternative exists Aim is to allow the patient to temporarily tolerate the drug in a safe manner (through immunologic or other non-immunologic mechanisms) Khan et al. JACI 2010;125:S

49 Drug desensitisation General principles The amount of drug tolerated by patient during the skin test determines a safe initial dose (usually 1/10,000 th of the final treatment dose) Double dose every 15 minutes until final dose Mild reactions occur in about 1/3 of patients, but no fatal reactions have been reported In order for patient to remain desensitised, it is necessary to continually administer medication Solensky R. Drug Hypersensitivity. Med Clin N Am 2006;90:

50

51 Outline 1. Background 2. SCAR 3. Mechanism of action 4. Assessment on history 5. Investigations 6. Drug desensitisation 7. Specific drugs

52 Specific drugs 1. Beta-lactams Penicillins Cephalopsorins 2. Sulfonamides 3. Perioperative 4. Radiocontrast media 5. Aspirin & NSAIDs

53 Specific drugs 1. Beta-lactams Penicillins Cephalopsorins 2. Sulfonamides 3. Perioperative 4. Radiocontrast media 5. Aspirin & NSAIDs

54 Beta-lactams: Penicillins Beta-lactam ring 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

55 Beta-lactams: Penicillins Thiazolidine ring 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

56 Beta-lactams: Penicillins R1 side chain 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

57 Structural similarities and differences of penicillin sidechains Baldo BA. Penicillins and cephalosporins as allergens structural aspects of recognition and cross-reactions. Clinical and Experimental Allergy 199;29:

58 Beta-lactams: Penicillins ~ 95 % 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6): Khan et al. (2010). Journal of Allergy and Clinical Immunology 125:S

59 Investigations Suggested reagent panel Classical penicillin reagents: PPL, MDM and benzylpenicillin Semi-synthetic penicillins: Amoxycillin and ampicillin Skin prick test Intradermal skin test Drug challenge

60 NPV of Penicillin testing Generally considered to be very high Large scale studies show that only 1-3% of skin test-negative patients develop a mild, self-limiting reaction when challenged to the drug Gadde et al. JAMA 1993; 270: (n = 775) Sogn et al. Arch Intern Med 1992; 152: (n = 726) Mendelson et al. JACI 1984; 73: (n = 240) Sullivan et al. JACI 1981; 68: (n = 740) Solensky, R. (2006). Medical Clinics of North America 90(1):

61 Cephalosporin cross-reactivity Beta-lactam ring 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

62 Cephalosporin cross-reactivity Thiazolidine ring Dihydrothiazine ring 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

63 Cephalosporin cross-reactivity R1 side chain: implicated in cross-reactivity 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

64 Cephalosporin cross-reactivity R2 side chain: disappears after betalactam ring opens 1. Solensky, R. (2006). Medical Clinics of North America 90(1): Gruchalla, R. S., M. Pirmohamed, et al. (2006). New England Journal of Medicine 354(6):

65 Cephalosporin cross-reactivity Historical 10% cross-reactivity a myth? Until 1982, compounds related to penicillin had been produced by using a cephalosporium mould and the cephalosporins included in the analyses were contaminated with penicillin 1 Patients were not proven to be penicillin-allergic (either through diagnostic testing or drug challenge) 4 Most 1 st gen cephalosporins have similar R-group side chains to benzylpenicillin, and this factor (rather than betalactam ring) may have led to cross-reactivity 2 1. Preger S and Healy B. BMJ 2007;335: Solensky R. Med Clin N Am ;90:

66 Cephalosporin cross-reactivity In a recent meta-analysis 6 studies of 2387 patients with penicillin allergy and 44,897 without Cross-reactivity was found to be related to cephalosporin generation 1 st generation OR 4.79 (95%CI ) 2 nd generation OR 1.13 (95%CI ) 3 rd generation OR 0.45 (95%CI ) Implications For life-threatening conditions where it is optimal to use a cephalosporin antibiotic in a penicillin-allergic patient Consider use of a 2 nd or 3 rd generation cephalosporin with a different side chain under suspicion 1. Preger S and Healy B. BMJ 2007;335:991.

67 Specific drugs 1. Beta-lactams Penicillins Cephalopsorins 2. Sulfonamides 3. Perioperative 4. Radiocontrast media 5. Aspirin & NSAIDs

68 Sulfonamides Pathogenesis Likely T-cell-mediated mechanism (rather than specific IgE or IgG antibodies) 1 Increased risk in HIV-positive patients, due to: altered drug metabolism (slow acetylation), relative glutathione deficiency and viral stimulation of cytochrome p450 and gamma-interferon 2 Clinical 2 Mostly causes delayed generalised maculopapular eruptions, associated with fever and pruritus 1. Choquet-Kastylevsky et al. Curr Alelrgy Asthma Rep 2002;2: Solensky R. Med Clin N Am 2006;90:

69 Solensky R. Med Clin N Am 2006;90: Strom et al. NEJM 2003;349:

70 Specific drugs 1. Beta-lactams Penicillins Cephalopsorins 2. Sulfonamides 3. Perioperative 4. Radiocontrast media 5. Aspirin & NSAIDs

71 Perioperative anaphylaxis Background Occurs in 1 every 1250 to 10,000 anaesthetics Causes Neuromuscular blocking agent (NMBA) 50-70% Latex allergy Antibiotic allergies Uncommon: hypnotic agents, opioids, colloids, aprotinin, protamine Increasingly reported: dyes, chlorhexidine, NSAIDs

72 Perioperative anaphylaxis NMBA Occurs in the induction phase of anaesthesia Commonly succinylchloine (depolarising NMBA) Cross-reactivity between NMBA is common (50-70%) in aminosteroid NMBA: pancuronium, vecuronium, rocuronium in benzylisoquinolone-derived NMBA: atracurium, cisatracurium (lowerst incidence of anaesthetic anaphylaxis) Latex allergy Contact urticaria: to latex gloves Anaphylaxis: occurs in the maintenance phase of anaesthesia Risk factors: multiple operations (abdo, gynae, ortho), atopic predisposition, spina bifida (VP shunt) Ix: SPT, sige, latex glove challenge

73 Local anaesthetics Benzoate esters Local anaesthetics Benzocaine Amides Bupivacaine Chloroprocaine Levobupivacaine Cocaine Lidocaine (lignocaine) Procaine Mepivacaine Proparacaine Ropivacaine Tetracaine (amethocaine) Prilocaine Cross-react with other esters Does not cross-react with amides. Does not cross-react with either other amides or esters. Khan DA and Solensky R. Drug allergy. Journal of Allergy and Clinical Immunology 2010;125:S

74 Specific drugs 1. Beta-lactams Penicillins Cephalopsorins 2. Sulfonamides 3. Perioperative 4. Radiocontrast media 5. Aspirin & NSAIDs

75 Radiocontrast media (RCM) Anaphylactoid reactions 1 1-3% of patients receiving ionic RCM <0.5% of patients receiving non-ionic RCM Severe life-threatening reactions % of patients receiving ionic RCM 0.04% of patients receiving non-ionic RCM Fatality rate 1-2 per 100,000 procedures 3 1. Wolf et al. Invest Radiol 1991;26: Katayama et al. Radiology 1990;175: Caro et al. AJR Am J Roentgenol 1991;156:825-32

76 Radiocontrast media (RCM) Anaphylactoid versus anaphylaxis Reaction not mediated by specific IgE antibodies RCM likely has direct effects on mast cells and basophils leads to direct degranulation and systemic mediator release Complement activation may also account for some reactions Solensky R. Med Clin N Am 2006;90:

77 Radiocontrast media (RCM) Management 1. Determine if the study is essential 2. Explain risks to patient 3. Ensure proper hydration 4. Use a non-ionic, iso-osmolar RCM 5. Pretreatment with corticosteroid and antihistamine Solensky R. Med Clin N Am 2006;90:

78 Specific drugs 1. Beta-lactams Penicillins Cephalopsorins 2. Sulfonamides 3. Perioperative 4. Radiocontrast media 5. Aspirin & NSAIDs

79 Aspirin

80 Type of reaction Aspirinexacerbated respiratory disease (AERD) Notes Occurs in up to 20% of adult asthmatic patients, more common in women, has an average onset of around 30 yo 1 Usually starts with rhinitis, progressing to sinusitis and nasal polyposis 1 Pathogenesis: aspirin leads to inhibition of COX-1 decrease PGE2 levels reduced inhibition of 5- lipoxygenase increased cysteinyl leukotrienes 2 Management: avoid both aspirin and NSAIDs; aggressive management of asthma and rhinitis 2 Exacerbation of chronic urticaria & angiodema Ingestion of NSAIDs that inhibit COX-1 can exacerbate chronic urticaria & angioedema 2 Most patients tolerate COX-2 inhibitors 2 Anaphylaxis Typically drug-specific and able to tolerate other NSAIDs 3 1. Stevenson DD. JACI 2006;118: Khan et al. JACI 2010;125:S Quiralte et al. J Investig Allergol Clin Immunol 2007;17:182-8.

81 Summary points 1. Severe cutaneous drug reactions SJS, TEN, AGEP, HSS (DRESS) Can cause significant morbidity and mortality Important to exclude these conditions as they present as contraindications for IDT and drug challenge 2. Investigations Commonly used: SPT, IDT and drug challenge Less useful: serum specific IgE, basophil activation assays and patch testing

82 Summary points 3. Penicillin allergy Majority (90%) of self-reported penicillin allergic patients are actually tolerant following evaluation and drug challenge IDT is performed to the Major determinant: benzylpenicilloyl Minor determinant Side chains: amoxycillin and ampicillin NPV for intradermal skin testing is good (97-99%)

83 Summary points 4. Penicillin and cross-reactivity with cephalosporins Previous 10% cross-reactivity rates are likely overestimated Cross-reactivity with cephalosporins are most likely due to similarities of R1-side chains (rather than sensitisation to beta-lactam ring) If skin testing is negative, patients have a high likelihood of tolerating a 3 rd generation cephalosporin